India: Highlights From Pharmacovigilance Risk Assessment Committee (PRAC) Meeting Held In May 2018

On May 18, 2018, the European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) concluded two referrals for Zinbryta (daclizumab beta) and Esmya (ulipristal acetate), maintained recommendation on hydroxyethyl-starch (HES) solutions for infusion and issued precautionary advice on HIV medicine Dolutegravir1. The resulting recommendations subsequent to PRAC meeting are:

1. PRAC confirms its recommendation to suspend hydroxyethyl-starch (HES) solutions for infusion in the European Union (EU)

PRAC has confirmed its recommendation to suspend marketing authorizations for hydroxyethyl starch (HES) solutions for infusion across the EU following a request from the European Commission to look into certain aspects related to it.

In January 2018, the PRAC recommended suspending the marketing authorizations for HES solutions for infusion because they continued to be used in critically ill patients and patients with sepsis despite restrictions introduced in 2013 to reduce the risk of kidney injury and death in such patients.

In April 2018, the European Commission requested the PRAC to consider whether suspending the marketing authorizations could result in an unmet medical need. It also requested the PRAC to consider the feasibility and likely effectiveness of additional risk minimization measures. After having assessed the relevant data on these specific aspects, the PRAC confirmed its previous recommendation that HES solutions for infusion should be suspended.

About Hydroxyethyl-Starch (HES)

HES solutions for infusion are used for the management of hypovolemia (low blood volume) caused by acute blood loss, where treatment with alternative infusion solutions known as 'crystalloids' alone is not considered to be sufficient. They are given by infusion (drip) into a vein and are used as blood volume expanders to prevent shock following acute bleeding. They belong to the class of medicines known as colloids. Besides blood products, there are two types of medicines used for plasma volume replacement: crystalloids and colloids. Colloids contain large molecules such as starch, whereas crystalloids, such as saline or Ringer's solutions, are pure electrolyte solutions.

2. PRAC recommends new measures to minimize risk of rare but serious liver injury with Esmya for fibroids

PRAC has completed its review of Esmya (ulipristal acetate), following reports of serious liver injury and has concluded that it may have contributed to the development of some cases of serious liver injury. The Committee has therefore, made the following recommendations to minimize this risk:

  • Esmya must not be used in women with known liver problems.
  • A liver function test should be performed before starting each treatment course and treatment must not be started if liver enzyme levels are more than 2 times the upper limit of normal.
  • Liver function tests should be performed once a month during the first two treatment courses and two to four weeks after stopping treatment. If the test is abnormal (liver enzyme levels more than 3 times the upper limit of normal), the monitor the patient.
  • Esmya should be used for more than one treatment course only in women who are not eligible for surgery. Women who are about to have surgery should continue to use only one course.
  • A card will be included in the box of the medicine to inform patients about the need for liver monitoring, and to contact their doctor should they develop symptoms of liver injury (such as tiredness, yellowing of the skin, darkening of the urine, nausea and vomiting).
  • Studies should be performed to determine the effects of Esmya on the liver and whether these measures are effectively minimizing the risks.

In February 2018, while the review was ongoing, the PRAC had issued temporary recommendations that no new patients should be started on Esmya. Having finalized its review, the Committee has now concluded that new patients can start treatment in line with the above recommendations to minimize the risk of liver injury.

About Esmya (ulipristal acetate)

Esmya works by attaching to the targets cells (receptors) that the hormone progesterone normally attaches to, preventing progesterone from having its effect. Since progesterone may promote the growth of fibroids, by preventing the effects of progesterone ulipristal acetate reduces the size of the fibroids. Esmya is used to treat moderate to severe symptoms of uterine fibroids (benign tumors of the womb). The medicine has been shown to be effective at reducing bleeding and anaemia, as well as the size of the fibroids.

3. PRAC review of Zinbryta confirms medicine's risks outweigh benefits

PRAC has confirmed that the multiple sclerosis medicine Zinbryta (daclizumab beta) poses a risk of serious and potentially fatal immune reactions affecting the brain, liver and other organs2. There are no immediate consequences of the PRAC's review as Zinbryta is no longer authorized in the EU.

On March 6, 2018, while the review was ongoing, the PRAC had recommended suspension of the marketing authorization of Zinbryta in the EU and a recall of the product from pharmacies and hospitals, following 12 reports of serious inflammatory brain disorders worldwide, including encephalitis and meningoencephalitis. On March 27 2018, the European Commission withdrew the marketing authorization of the medicine at the request of the marketing authorization holder Biogen Idec Ltd.

About Daclizumab (Zinbryta)

Zinbryta (Daclizumab) was authorised in 2016 for treating relapsing forms of multiple sclerosis. Following a 2017 review of the medicine's effects on the liver, the use of the medicine was restricted to patients who had tried at least two other disease-modifying treatments and could not be treated with any other multiple sclerosis treatments. To date over 8,000 patients have been treated with Daclizumab worldwide. The majority of EU patients have been treated in Germany.

4. New study suggests risk of birth defects in babies born to women on HIV medicine Dolutegravir

EMA's Pharmacovigilance Risk Assessment Committee (PRAC) has issued precautionary advice regarding risk of birth defects in babies born to women on HIV medicine Dolutegravir3. As a precaution, healthcare professionals in the EU are advised of the following:

  • Do not prescribe Dolutegravir for women of child bearing potential who are trying to become pregnant.
  • Exclude pregnancy in women of child bearing potential before starting Dolutegravir.
  • Advise women of child bearing potential who are taking Dolutegravir to use effective contraception throughout treatment.
  • If pregnancy is confirmed in the first trimester while a woman is taking Dolutegravir, switch to an alternative treatment unless there is no suitable alternative.

The PRAC is evaluating preliminary results from a study which found four cases of birth defects such as spina bifida (malformed spinal cord) in babies born to mothers who became pregnant while taking the HIV medicine Dolutegravir. Women who have been prescribed Dolutegravir should not stop taking their medicine without first consulting their doctor.

About Dolutegravir

Dolutegravir is an integrase inhibitor. This means that it blocks an enzyme called integrase that is needed by the HIV virus to make new copies of itself in the body. When it is given with other medicines, it helps to prevent the spread of HIV and keep the amount of the virus in the blood at a low level. Dolutegravir does not cure HIV infection or AIDS, but it may hold off damage to the immune system and the development of infections and diseases associated with AIDS.


The PRAC recommendation for HES will be sent to the CMDh (Coordination Group for Mutual Recognition and Decentralised Procedures - Human) for further consideration. The PRAC's referrals for Esmya and Zinbryta will now be sent to the Committee for Medicinal Products for Human Use (CHMP) for the adoption of EMA's final opinion, and further to the European Commission for a final legal decision. Moreover, the EMA's review of Dolutegravir is ongoing, and the agency will update the recommendations as necessary when it concludes its assessment.





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